UsnRNP trafficking is regulated by stress granules and compromised by mutant ALS proteins

Rossi, Simona; Rompietti, Valentina; Antonucci, Ylenia; Giovannini, Daniela; Scopa, Chiara; Scaricamazza, Silvia; Scardigli, Raffaella; Cestra, Gianluca; Serafino, Annalucia; Carrı̀, Maria Teresa; D’Ambrosi, Nadia; Cozzolino, Mauro

doi:10.1016/j.nbd.2020.104792

Cited by 19 publications

(26 citation statements)

References 35 publications

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“…The C9ORF72 repeat expansion produces dipeptide repeat (DPR) proteins through non-conventional translation mechanisms (Cheng et al, 2019). These DPR proteins have been shown to exhibit toxic effects by interfering with nucleo-cytoplasmic transport and disassembling Cajal bodies and nuclear gems (Simona et al, 2020).…”

Section: Als Geneticsmentioning

confidence: 99%

“…5-10% of familial cases of ALS have mutations in TDP-43 and despite lacking known mutations 97% of sporadic cases have TDP-43 inclusion bodies in their brain and spinal cord (Prasad et al, 2019). The exact molecular mechanism by which cytoplasmic TDP-43 results in neurodegeneration is unclear, but it has been shown to accumulate in the mitochondria (Wang et al, 2016), impair overall nucleocytoplasmic trafficking (Simona et al, 2020), and associate with FIGURE 1 | A SGs dysregulation associates with multiple cellular phenotypes in ALS. SGs are hypothesized to act as a seeding mechanism for the pathological aggregations of TDP43 and FUS.…”

Section: Als Geneticsmentioning

confidence: 99%

“…These genes are found in a number of different pathways that potentially contribute to disease progression. These pathways include: axonal transport, the unfolded protein response, endoplasmic reticulum stress (Dervishi et al, 2018), autophagy and mitophagy (Evans and Holzbaur, 2019), the integrated stress response (ISR), nucleocytoplasmic trafficking, alternative splicing (Simona et al, 2020), and RNA metabolism (Fan and Leung, 2016).…”

Section: Introductionmentioning

confidence: 99%

“…The formation of SGs prevents the formation of NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasomes and protects the cell from undergoing pyroptosis (Samir et al, 2019). The formation of SGs impacts the numbers of other membraneless organelles such as Cajal bodies and nuclear gems (Simona et al, 2020). SGs also inhibit translation during stressed conditions by sequestering RNA.…”

Section: Introductionmentioning

confidence: 99%

“…SGs also inhibit translation during stressed conditions by sequestering RNA. The consequences of chronic cellular stress have not been fully defined, but have been strongly associated with neurodegeneration and other pathologies (Simona et al, 2020). In situations of chronic cellular stress, including aging, SGs can become persistent structures.…”

Section: Introductionmentioning

confidence: 99%

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Stress Granule Dysregulation in Amyotrophic Lateral Sclerosis

Dudman

2020

Front. Cell. Neurosci.

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Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with no current cure. ALS causes degeneration of both upper and lower motor neurons leading to atrophy of the innervating muscles and progressive paralysis. The exact mechanism of the pathology of ALS is unknown. However, 147 genes have been identified that are causative, associated with, or modify disease progression. While the causative mechanism is unknown, a number of pathological processes have been associated with ALS. These include mitochondrial dysfunction, protein accumulation, and defects in RNA metabolism. RNA metabolism is a complicated process that is regulated by many different RNA-binding proteins (RBPs). A small defect in RNA metabolism can produce results as dramatic as determining cell survival. Stress granules (SGs) control RNA translation during stressed conditions. This is a protective reaction, but in conditions of chronic stress can become pathogenic. SGs are even hypothesized to act as a seeding mechanism for the pathological aggregation of proteins seen in many neurodegenerative diseases, including TAR DNA-binding protein 43 (TDP-43) in ALS. In this review, we will be summarizing the current findings of SG pathology in ALS. We also focus on the role of SG dysregulation in protein aggregate formation and mitochondrial dysfunction. In addition, we outline therapeutic strategies that target SG components in ALS.

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Section: Als Geneticsmentioning

confidence: 99%